KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming.

Abstract

Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multiomics analyses. We found that a deficiency of KMT2C, a histone H3 lysine 4 methyltransferase frequently mutated in extensive-stage SCLC, promoted multiple-organ metastases in mice. Metastatic and KMT2C-deficient SCLC displayed both histone and DNA hypomethylation. Mechanistically, KMT2C directly regulated the expression of DNMT3A, a de novo DNA methyltransferase, through histone methylation. Forced DNMT3A expression restrained metastasis of KMT2C-deficient SCLC through repressing metastasis-promoting MEIS/HOX genes. Further, S-(5'-adenosyl)-L-methionine, the common cofactor of histone and DNA methyltransferases, inhibited SCLC metastasis. Thus, our study revealed a concerted epigenetic reprogramming of KMT2C- and DNMT3A-mediated histone and DNA hypomethylation underlying SCLC metastasis, which suggested a potential epigenetic therapeutic vulnerability.

• Authors: Feifei Na, Xiangyu Pan, Jingyao Chen, Xuelan Chen, Manli Wang, Pengliang Chi, Liting You, Lanxin Zhang, Ailing Zhong, Lei Zhao, Siqi Dai, Mengsha Zhang, Yiyun Wang, Bo Wang, Jianan Zheng, Yuying Wang, Jing Xu, Jian Wang, Baohong Wu, Mei Chen, Hongyu Liu, Jianxin Xue, Meijuan Huang, Youling Gong, Jiang Zhu, Lin Zhou, Yan Zhang, Min Yu, Panwen Tian, Mingyu Fan, Zhenghao Lu, Zhihong Xue, Yinglan Zhao, Hanshuo Yang, Chengjian Zhao, Yuan Wang, Junhong Han, Shengyong Yang, Dan Xie, Lu Chen, Qian Zhong, Musheng Zeng, Scott W Lowe, You Lu, Yu Liu, Yuquan Wei, Chong Chen
• Journal: Nature cancer (Nat Cancer) Vol. 3 Issue 6 Pg. 753-767 (06 2022) ISSN: 2662-1347 [Electronic] England
• PMID: 35449309 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Dnmt3a protein, mouse
• Histones
• DNA
• DNA Modification Methylases
• Methyltransferases
• DNA (Cytosine-5-)-Methyltransferases
• DNA Methyltransferase 3A
• Histone-Lysine N-Methyltransferase
• MLL3 protein, mouse

Topics

• Animals
• DNA (metabolism)
• DNA (Cytosine-5-)-Methyltransferases (genetics)
• DNA Methylation (genetics)
• DNA Methyltransferase 3A (genetics)
• DNA Modification Methylases (genetics)
• Epigenesis, Genetic (genetics)
• Histone-Lysine N-Methyltransferase (deficiency, genetics)
• Histones (genetics)
• Lung Neoplasms (genetics, pathology)
• Methyltransferases (genetics)
• Mice
• Small Cell Lung Carcinoma (genetics, secondary)